title: Cellular delivery of siRNA and antisense oligonucleotides via receptor-mediated endocytosis.
abstract: BACKGROUND
  There is great potential for antisense and siRNA oligonucleotides to become mainstream therapeutic entities thanks to their high specificity and wide therapeutic target space compared with small molecules. Despite this potential, the pharmacological targets within the cells are less accessible to oligonucleotides that are hydrophilic and often charged. Oligonucleotides access their intracellular targets mainly by means of endocytosis, but only a fraction of them reach their targets, as delivery requires functional synergy of cellular uptake and intracellular trafficking.
  
  
  METHODS
  This review provides an update on the progress of receptor-targeted delivery of oligonucleotides over the last 15 years and summarizes various targeting moieties for oligonucleotide delivery and coupling strategies. To inspire new strategies that can lead to oligonucleotides in the clinic, this review highlights how oligonucleotides successfully reach their intracellular targets by means of receptor-mediated endocytosis.
  
  
  CONCLUSIONS
  Understanding the mechanisms of oligonucleotide internalization has led to greater cellular uptake and superior endosomal release through the rational design of receptor-targeted delivery systems. Further improvements will again depend on a better understanding of the intracellular trafficking of oligonucleotides.
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. xming@email.unc.edu
authors.forename: Xin
authors.initials: X
authors.lastname: Ming
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface